2-241735267-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_152783.5(D2HGDH):c.43C>G(p.Arg15Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00608 in 1,518,798 control chromosomes in the GnomAD database, including 403 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R15R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0084 ( 51 hom., cov: 34)

Exomes 𝑓: 0.0058 ( 352 hom. )

Consequence

D2HGDH
NM_152783.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.861

Publications

6 publications found

Variant links:

Genes affected

D2HGDH (HGNC:28358): (D-2-hydroxyglutarate dehydrogenase) This gene encodes D-2hydroxyglutarate dehydrogenase, a mitochondrial enzyme belonging to the FAD-binding oxidoreductase/transferase type 4 family. This enzyme, which is most active in liver and kidney but also active in heart and brain, converts D-2-hydroxyglutarate to 2-ketoglutarate. Mutations in this gene are present in D-2-hydroxyglutaric aciduria, a rare recessive neurometabolic disorder causing developmental delay, epilepsy, hypotonia, and dysmorphic features. [provided by RefSeq, Jul 2008]

D2HGDH Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
D-2-hydroxyglutaric aciduria 1
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
D-2-hydroxyglutaric aciduria
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

D2HGDH links:

ENSG00000215692 (HGNC:):

ENSG00000215692 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001637876).

BP6

Variant 2-241735267-C-G is Benign according to our data. Variant chr2-241735267-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 158420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.105 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152783.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
D2HGDH	NM_152783.5	MANE Select	c.43C>G	p.Arg15Gly	missense	Exon 2 of 10	NP_689996.4
D2HGDH	NM_001352824.2		c.-502C>G		5_prime_UTR	Exon 2 of 10	NP_001339753.1
D2HGDH	NM_001287249.2		c.-111+572C>G		intron	N/A	NP_001274178.1	B5MCV2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
D2HGDH	ENST00000321264.9	TSL:1 MANE Select	c.43C>G	p.Arg15Gly	missense	Exon 2 of 10	ENSP00000315351.4	Q8N465-1
D2HGDH	ENST00000436747.5	TSL:1	n.43C>G		non_coding_transcript_exon	Exon 2 of 12	ENSP00000400212.1	F8WCF9
D2HGDH	ENST00000951632.1		c.43C>G	p.Arg15Gly	missense	Exon 2 of 12	ENSP00000621691.1

Frequencies

GnomAD3 genomes

AF:

0.00840

AC:

1278

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00263

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0458

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0507

Gnomad SAS

AF:

0.00270

Gnomad FIN

AF:

0.00952

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.0294

AC:

3407

AN:

115976

AF XY:

0.0229

show subpopulations

Gnomad AFR exome

AF:

0.00378

Gnomad AMR exome

AF:

0.121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0480

Gnomad FIN exome

AF:

0.0134

Gnomad NFE exome

AF:

0.00138

Gnomad OTH exome

AF:

0.0206

GnomAD4 exome

AF:

0.00582

AC:

7957

AN:

1366538

Hom.:

352

Cov.:

AF XY:

0.00539

AC XY:

3636

AN XY:

674148

show subpopulations

African (AFR)

AF:

0.00137

AC:

AN:

29226

American (AMR)

AF:

0.108

AC:

3649

AN:

33696

Ashkenazi Jewish (ASJ)

AF:

0.0000417

AC:

AN:

23968

East Asian (EAS)

AF:

0.0680

AC:

2346

AN:

34496

South Asian (SAS)

AF:

0.00169

AC:

130

AN:

77004

European-Finnish (FIN)

AF:

0.0125

AC:

428

AN:

34180

Middle Eastern (MID)

AF:

0.000988

AC:

AN:

4048

European-Non Finnish (NFE)

AF:

0.000896

AC:

961

AN:

1072964

Other (OTH)

AF:

0.00699

AC:

398

AN:

56956

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

416

831

1247

1662

2078

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

184

276

368

460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00839

AC:

1278

AN:

152260

Hom.:

Cov.:

AF XY:

0.00936

AC XY:

697

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00262

AC:

109

AN:

41572

American (AMR)

AF:

0.0458

AC:

700

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.0509

AC:

263

AN:

5168

South Asian (SAS)

AF:

0.00270

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00952

AC:

101

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00101

AC:

AN:

68010

Other (OTH)

AF:

0.0104

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

125

188

250

313

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00166

Hom.:

Bravo

AF:

0.0134

ExAC

AF:

0.0105

AC:

1001

Asia WGS

AF:

0.0250

AC:

AN:

3472

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

D-2-hydroxyglutaric aciduria 1 (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.041

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.48

MetaRNN

Benign

0.0016

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.4

PhyloP100

0.86

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.0

REVEL

Benign

0.28

Sift

Benign

0.049

Sift4G

Uncertain

0.014

Polyphen

0.0

Vest4

0.14

MPC

0.51

ClinPred

0.0045

GERP RS

0.25

Varity_R

0.10

gMVP

0.60

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over